The formation of defects within additive-manufactured (AM) components is a major concern for critical structural and cyclic load applications. Thus, understanding the mechanisms of defect formation ...in fusion-based processes is important for prescribing the appropriate process parameters specific to the alloy system and selected processing technique. This article discusses the formation of defects within metal additive manufacturing, namely fusion-based processes and solid-state/sintering processes. Defects observed in fusion-based processes include lack of fusion, keyhole collapse, gas porosity, solidification cracking, solid-state cracking, and surface-connected porosity. The types of defects in solid-state/sintering processes are sintering porosity and improper binder burnout. The article also discusses defect-mitigation strategies, such as postprocess machining, surface treatment, and postprocessing HIP, to eliminate defects detrimental to properties from the as-built condition. The use of noncontact thermal, optical, and ultrasound techniques for inspecting AM components are also considered. The final section summarizes the knowledge gap in our understanding of the defects observed within AM components.
We report the long-term follow-up of the efficacy and safety of islet transplantation in seven type 1 diabetic subjects from the United States enrolled in the multicenter international Edmonton ...Protocol who had persistent islet function after completion of the Edmonton Protocol. Subjects were followed up to 12 years with serial testing for sustained islet allograft function as measured by C-peptide. All seven subjects demonstrated continued islet function longer than a decade from the time of first islet transplantation. One subject remained insulin independent without the need for diabetic medications or supplemental transplants. One subject who was insulin-independent for over 8 years experienced graft failure 10.9 years after the first islet transplant. The remaining six subjects demonstrated continued islet function upon trial completion, although three had received a supplemental islet transplant each. At trial completion, five subjects were receiving insulin and two remained insulin independent, although one was treated with liraglutide. The median hemoglobin A1c was 6.3% (45 mmol/mol). All subjects experienced progressive decline in the C-peptide/glucose ratio. No patients experienced severe hypoglycemia, opportunistic infection, or lymphoma. Thus, although the rate and duration of insulin independence was low, the Edmonton Protocol was safe in the long term. Alternative approaches to islet transplantation are under investigation.
In higher income countries, social disadvantage is associated with higher arthritis prevalence; however, less is known about arthritis prevalence or determinants in low to middle income countries ...(LMICs). We assessed arthritis prevalence by age and sex, and marital status and occupation, as two key parameters of socioeconomic position (SEP), using data from the World Health Organization Study on global AGEing and adult health (SAGE).
SAGE Wave 1 (2007-10) includes nationally-representative samples of older adults (≥50 yrs), plus smaller samples of adults aged 18-49 yrs., from China, Ghana, India, Mexico, Russia and South Africa (n = 44,747). Arthritis was defined by self-reported healthcare professional diagnosis, and a symptom-based algorithm. Marital status and education were self-reported. Arthritis prevalence data were extracted for each country by 10-year age strata, sex and SEP. Country-specific survey weightings were applied and weighted prevalences calculated.
Self-reported (lifetime) diagnosed arthritis was reported by 5003 women and 2664 men (19.9% and 14.1%, respectively), whilst 1220 women and 594 men had current symptom-based arthritis (4.8% and 3.1%, respectively). For men, standardised arthritis rates were approximately two- to three-fold greater than for women. The highest rates were observed in Russia: 38% (95% CI 36%-39%) for men, and 17% (95% CI 14%-20%) for women. For both sexes and in all LMICs, arthritis was more prevalent among those with least education, and in separated/divorced/widowed women.
High arthritis prevalence in LMICs is concerning and may worsen poverty by impacting the ability to work and fulfil community roles. These findings have implications for national efforts to prioritise arthritis prevention and management, and improve healthcare access in LMICs.
Juno's highly inclined orbits provide opportunities to sample high‐latitude magnetic field lines connected to the orbit of Io, among the other Galilean satellites. Its payload offers both ...remote‐sensing and in‐situ measurements of the Io‐Jupiter interaction. These are at discrete points along Io's footprint tail and at least one event (12th perijove) was confirmed to be on a flux tube Alfvénically connected to Io, allowing for an investigation of how the interaction evolves down‐tail. Here we present Alfvén Poynting fluxes and field‐aligned current densities along field lines connected to Io and its orbit. We explore their dependence as a function of down‐tail distance and show the expected decay as seen in UV brightness and electron energy fluxes. We show that the Alfvén Poynting and electron energy fluxes are highly correlated and related by an efficiency that is fully consistent with acceleration from Alfvén wave filamentation via a turbulent cascade process.
Plain Language Summary
Io and Jupiter are electrodynamically coupled resulting in the Io footprint tail. This is one of the most persistent, stable, and recognizable features of Jupiter's aurora. The Juno spacecraft routinely samples magnetic field lines connected to Io's orbit, allowing for an investigation of this powerful coupling. We use data recorded by Juno to estimate a proxy for the strength of this interaction, that is, electromagnetic energy, and show its dependence downstream of Io and how the interaction decays. We further show that the available electromagnetic energy and electron energy are intimately linked, suggesting a transfer of energy between wave and particles. This is the basis upon which electrons end up precipitating into Jupiter's upper atmosphere and generate some of the brightest auroras.
Key Points
Alfvénic Poynting fluxes and electron energy fluxes are highly correlated on magnetic field lines connected to Io's orbit
The efficiency in the Main Alfvén Wing is ∼10%, fully consistent with Alfvén wave filamentation via a turbulent cascade process
Field‐aligned current densities are quantified and exhibit a decay in magnitude down‐tail of Io
Objective
To examine oral complications 6 months after modern radiation therapy (RT) for head and neck cancer (HNC).
Methods
Prospective multicenter cohort study of patients with HNC receiving ...intensity‐modulated radiation therapy or more advanced RT. Stimulated whole salivary flow, maximal mouth opening, oral mucositis, oral pain, oral health‐related quality of life (OH‐QOL), and oral hygiene practices were measured in 372 subjects pre‐RT and 216 subjects at 6 months from the start of RT.
Results
Mean stimulated whole salivary flow declined from 1.09 to 0.47 ml/min at 6 months (p < .0001). Mean maximal mouth opening reduced from 45.58 to 42.53 mm at 6 months (p < .0001). 8.1% of subjects had some oral mucositis at 6 months, including 3.8% with oral ulceration. Mean overall pain score was unchanged. OH‐QOL was reduced at 6 months, with changes related to dry mouth, sticky saliva, swallowing solid foods, and sense of taste (p ≤ .0001). At 6 months, there was greater frequency of using dental floss and greater proportion using supplemental fluoride (p < .0001).
Conclusions
Despite advances in RT techniques, patients with HNC experience oral complications 6 months after RT, with resulting negative impacts on oral function and quality of life.
Abstract
Silicon (Si) is one of the most abundant elements on Earth, and it is the most widely used semiconductor. Despite extensive study, some properties of Si, such as its behaviour under dynamic ...compression, remain elusive. A detailed understanding of Si deformation is crucial for various fields, ranging from planetary science to materials design. Simulations suggest that in Si the shear stress generated during shock compression is released via a high-pressure phase transition, challenging the classical picture of relaxation via defect-mediated plasticity. However, direct evidence supporting either deformation mechanism remains elusive. Here, we use sub-picosecond, highly-monochromatic x-ray diffraction to study (100)-oriented single-crystal Si under laser-driven shock compression. We provide the first unambiguous, time-resolved picture of Si deformation at ultra-high strain rates, demonstrating the predicted shear release via phase transition. Our results resolve the longstanding controversy on silicon deformation and provide direct proof of strain rate-dependent deformation mechanisms in a non-metallic system.
The aim of this multicentre, longitudinal study was to determine salivary changes in relation to oral mucositis (OM) in multiple myeloma patients following high-dose melphalan and autologous ...hematopoietic stem cell transplantation (ASCT). Unstimulated and stimulated whole-mouth saliva samples (UWS and SWS) were collected before ASCT, 1×/wk during the hospitalisation phase, and 3 and 12 months post-ASCT. During the hospitalisation period OM was scored 3×/wk (WHO system). Flow rate, pH, total protein concentration (Nanodrop), albumin, lactoferrin, neutrophil defensin-1 (HNP1), total IgA and S100A8/A9 (ELISA) were determined. Mixed models were used to evaluate differences between ulcerative (u)OM (≥2 WHO, n = 20) and non-uOM (n = 31) groups. Until 18 days after ASCT, flow rate, pH, total IgA and HNP1 levels decreased in UWS and/or SWS, while log lactoferrin levels were significantly increased (UWS: p = 0.016 95% CI 0.36, 3.58, SWS: p < 0.001 95% CI 1.14, 3.29). Twelve months post-ASCT, salivary protein levels were similar to baseline except for log total IgA, which was higher (UWS: p < 0.001 95% CI 0.49, 1.29, SWS: p < 0.001 95% CI 0.72, 1.45). No differences between uOM and non-uOM groups were observed. Changes in salivary proteins indicated an inflammatory reaction in salivary glands coinciding with mucosal and systemic reactions in response to high-dose melphalan.
In HIV-1-infected individuals on currently recommended antiretroviral therapy (ART), viremia is reduced to <50 copies of HIV-1 RNA per milliliter, but low-level residual viremia appears to persist ...over the lifetimes of most infected individuals. There is controversy over whether the residual viremia results from ongoing cycles of viral replication. To address this question, we conducted 2 prospective studies to assess the effect of ART intensification with an additional potent drug on residual viremia in 9 HIV-1-infected individuals on successful ART. By using an HIV-1 RNA assay with single-copy sensitivity, we found that levels of viremia were not reduced by ART intensification with any of 3 different antiretroviral drugs (efavirenz, lopinavir/ritonavir, or atazanavir/ritonavir). The lack of response was not associated with the presence of drug-resistant virus or suboptimal drug concentrations. Our results suggest that residual viremia is not the product of ongoing, complete cycles of viral replication, but rather of virus output from stable reservoirs of infection.
Evidence suggests that 30–50% of patients suffering from major depressive disorder (MDD) are classified as suffering from treatment resistant depression (TRD) as they have an inadequate response to ...standard antidepressants. A key feature of this patient population is the increased incidence of co-morbid symptoms like anxiety and pain. Recognizing that current standards of care are largely focused on monoaminergic mechanisms of action (MOAs), innovative approaches to drug discovery for TRD are targeting glutamate hyperfunction.
Here we describe the in vitro and in vivo profile of GRN-529, a novel negative allosteric modulator (NAM) of metabotropic glutamate receptor 5 (mGluR5). In cell based pharmacology assays, GRN-529 is a high affinity (Ki 5.4 nM), potent (IC50 3.1 nM) and selective (>1000-fold selective vs mGluR1) mGluR5 NAM. Acute administration of GRN-529 (0.1–30 mg/kg p.o.) had dose-dependent efficacy across a therapeutically relevant battery of animal models, comprising depression (decreased immobility time in tail suspension and forced swim tests) and 2 of the co-morbid symptoms overrepresented in TRD, namely anxiety (attenuation of stress-induced hyperthermia, and increased punished crossings in the four plate test) and pain (reversal of hyperalgesia due to sciatic nerve ligation or inflammation). The potential side effect liability of GRN-529 was also assessed using preclinical models: GRN-529 had no effect on rat sexual behavior or motor co-ordination (rotarod), however it impaired cognition in mice (social odor recognition). Efficacy and side effects of GRN-529 were compared to standard of care agents (antidepressant, anxiolytic or analgesics) and the tool mGluR5 NAM, MTEP. To assess the relationship between target occupancy and efficacy, ex vivo receptor occupancy was measured in parallel with efficacy testing. This revealed a strong correlation between target engagement, exposure and efficacy across behavioral endpoints, which supports the potential translational value of PET imaging to dose selection in patients. Collectively this broad spectrum profile of efficacy of GRN-529 supports our hypothesis that negative allosteric modulation of mGluR5 could represent an innovative therapeutic approach to the treatment of TRD.
This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’.
► We describe GRN-529, a novel potent and selective mGluR5 negative allosteric modulator. ► GRN-529 had efficacy in rodent preclinical antidepressant, anxiolytic and analgesic models. ► This efficacy profile lines up with core and co-morbid symptoms over-represented in treatment resistant depressed patients. ► GRN-529 has a favorable side effect profile with respect to sexual dysfunction and motor co-ordination. ► Efficacy and side effects were correlated to target engagement by measuring receptor occupancy after behavioral testing.
This study examined (1) descriptive patterns in perceived environmental and policy determinants of physical activity and (2) associations between these factors and behavior.
A cross-sectional study ...was conducted from 1999 to 2000 among US adults; individuals at lower income levels were oversampled.
Availability of areas for physical activity was generally higher among men than among women. The 4 most commonly reported personal barriers were lack of time, feeling too tired, obtaining enough exercise at one's job, and no motivation to exercise. Neighborhood characteristics, including the presence of sidewalks, enjoyable scenery, heavy traffic, and hills, were positively associated with physical activity. There was a high level of support for health policy-related measures. Up to one third of individuals who had used environmental supports reported an increase in physical activity.
An array of environmental and policy determinants, particularly those related to the physical environment, are associated with physical activity and should be taken into account in the design of interventions.
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